Iontophoresis, according to Dorland's Illustrated Medical Dictionary, is defined to be "the introduction, by means of electric current, of ions of soluble salts into the tissues of the body for therapeutic purpose." Iontophoretic devices have been known since the early 1900's. British patent specification No. 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices known to the art at that time, namely the requirement of a special low tension (low voltage) source of current which meant that the patient needed to be immobilized near such source. The device of that British specification was made by forming, from the electrodes and the material containing the medicament or drug to be delivered transdermally, a galvanic cell which itself produced the current necessary for iontophoretically delivering the medicament. This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily activities.
More recently, a number of United States patents have issued in the iontophoresis field, indicating a renewed interest in this mode of drug delivery. For example, U.S. Pat. No. 3,991,755 issued to Vernon et al; U.S. Pat. No. 4,141,359 issued to Jacobsen et al; U.S. Pat. No. 4,398,545 issued to Wilson; and U.S. Pat. No. 4,250,878 issued to Jacobsen disclose examples of iontophoretic devices and some applications thereof. The iontophoresis process has been found to be useful in the transdermal administration of medicaments or drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, insulin and many other drugs. Perhaps the most common use of iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates sweat production; the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
In presently known iontophoretic devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by electrodiffusion. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, then the negative electrode will be the active electrode and the positive electrode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the positive electrode (the anode) can drive a positively charged ionic substance into the body while the negative electrode (the cathode) can drive a negatively charged ionic substance into the body.
It is also known that iontophoretic delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process called electro-osmosis. Electro-osmosis is the volume flow of a liquid (e.g., a liquid containing the uncharged drug or agent) through the skin induced by the presence of an electric field imposed across the skin.
Furthermore, existing iontophoresis devices generally require a reservoir or source of the beneficial agent (which is preferably an ionized or ionizable agent or a precursor of such agent) to be iontophoretically delivered into the body. Examples of such reservoirs or sources of ionized or ionizable agents include a pouch as described in the previously mentioned Jacobsen U.S. Pat. No. 4,250,878, or a pre-formed gel body as described in Webster U.S. Pat. No. 4,382,529. Such drug reservoirs are electrically connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired agents.
There is a continuing need to develop an iontophoretic drug delivery device with improved characteristics and specifically with improved control over the drug delivery profile. Conventional microporous ultrafiltration-type membranes have been used to control the rate at which agent (i.e., drug) is released from a passive transdermal or transmucosal delivery device. Passive delivery devices deliver drug or other beneficial agent through the skin by diffusion. These passive delivery devices are driven by a drug concentration gradient (i.e., the concentration of drug in the drug reservoir of the device is greater than the concentration of drug in the skin of the patient). While conventional semipermeable ultrafiltration-type membranes have been suggested for use in iontophoretic delivery devices (e.g., in Parsi U.S. Pat. No. 4,731,049 and Sibalis U.S. Pat. No. 4,460,689) they have been found to be unsuitable for use in portable battery-powered iontophoretic delivery devices because of their high electrical resistivity (i.e., resistivity to ionic transport). Therefore, there is a need for a membrane having low electrical resistivity which may be used to control the rate at which agent is released from an electrically-powered iontophoretic agent delivery device.
There is also a need for a control membrane in an iontophoretic drug delivery device which can substantially prevent passive release of drug from the device when the device is placed on the patient's body. Such a membrane also would have important advantages when delivering highly potent drugs which might otherwise become harmful to the patient if present at greater than predetermined plasma concentrations. The membrane would prevent too much drug from being delivered, if for example, the delivery device is inadvertently placed on cut or abraded skin or on a body surface which has somehow been compromised. Further, such a membrane would permit safer handling of the device during manufacture and use.
Such a membrane, by eliminating or at least greatly reducing passive transport, would also allow the drug delivery rate to be substantially reduced when the power to the iontophoretic delivery device is turned off. Thus, the membrane would have particular utility in both iontophoretic delivery devices which are turned on and off by the patient for "on-demand" delivery of a beneficial agent (e.g., an anesthetic or other pain killing agent) or in iontophoretic delivery devices having a control circuit which alternates drug delivery pulses with periods during which no drug is delivered. Since the membrane would substantially reduce the rate at which beneficial agent is passively delivered from the device, the membrane would allow a more precise patterned drug delivery profile.
Along with the growing interest in the development of iontophoretic delivery devices, there has been a growing need for improved techniques of testing the performance characteristics of the devices. For example, state of the art techniques for measuring the in vitro agent release rates of passive transdermal systems are inadequate for testing the agent release rates of electrically powered iontophoretic delivery devices. Typically, such testing involves placing the passive delivery system on either a section of human cadaver skin or on a synthetic membrane which exhibits passive drug diffusion characteristics similar to that of skin. Examples of such membranes include a copolyester membrane sold by E.I. DuPont de Nemours of Wilmington, Del. under the tradename Hytrel.RTM. or an ethylene vinyl acetate copolymer such as EVA 9. The other side of the skin or membrane is in contact with an aqueous receiving medium. The drug is delivered from the passive delivery system through the skin or membrane into the aqueous medium where it can be collected for measurement. Unfortunately, these passive delivery test membranes do not closely approach the electrically-assisted ion transport characteristics of skin and therefore cannot be used to accurately predict the in vivo performance characteristics of an iontophoretic delivery device. In addition, cadaver skin exhibits an unacceptably high level of variation (when measuring device stability) and sufficient quantities of cadaver skin are not always readily available. Thus, there is a need for a synthetic membrane which exhibits electrically-assisted ionic transport properties similar to those of skin and which therefore can be used to test the performance characteristics of an iontophoretic agent delivery device in vitro.